ABSTRACT Deposition of antibody-antigen immune complexes (IC) in tissues underlies the pathogenesis of a range of human autoimmune diseases from glomerulonephritis, SLE and arthritis, to transplantation rejection. Infiltrating leukocytes are the cause of inflammatory tissue damage. The primary objective of this competing renewal remains an in depth study of the mechanisms of IC mediated neutrophil recruitment and injury. Receptors for IgG, collectively known as FcRs, mediate the interaction of antibodies with effector cells. In the current grant period, we provide several lines of evidence that the low affinity activating neutrophil FcRs in mice, which preferentially complex with IgG-ICs, directly mediate neutrophil accumulation. Neutrophil FcRs and the leukocyte specific CD18 integrins cooperated to promote IC induced neutrophil slow rolling, adhesion and transmigration, and TNF priming of neutrophils enhanced these processes. There are notable structural differences between neutrophil human and mouse low affinity activating FcRs. Mice express FcRIII and FcRIV which complex with the common -chain to signal while human neutrophils express FcRIIA with the ITAM signaling and ligand binding domain in a single polypeptide chain, and a unique GPI-linked FcRIIIB. To examine the physiological functions, and the relative roles of the human neutrophil FcRs in vivo, we expressed human FcRIIIB and FcRIIA selectively in neutrophils of mice lacking the common -chain (-/-) and thus endogenous activating FcRs. -/- mice failed to develop anti-glomerular basement membrane induced progressive glomerulonephritis and soluble IC induced Reverse Passive Arthus reaction as expected. In contrast, mice expressing hFcRIIA on neutrophils displayed significant tissue injury. Moreover, mice expressing either hFcRIIIB or hFcRIIA exhibited significant tissue neutrophil accumulation in both models. Using intravital microscopy, we demonstrate that neutrophil FcRIIA and FcRIIIB play specialized context-dependent roles in IC-mediated neutrophil slow rolling, adhesion and transmigration. From these, and related observations, we hypothesize that FcRIIA and FcRIIIB serve distinct nonredundant functions in response to ICs, which are differentially regulated. We propose that 1) FcRIIIB tethering to ICs, supported by CD18 integrins serves a homeostatic role in clearing intravascular ICs, while 2) FcRIIA mediated recruitment and associated injury is regulated by cytokines, resident mast cells and macrophages, and requires its ITAM motif. In this proposal we will rigorously test these hypothesis using our humanized FcR transgenics, mouse lines deficient in mast cells or macrophages, and cell reconstitution approaches coupled with well-characterized in vivo models of IC induced inflammation and intravital microscopy. We anticipate that the new information provided by this proposal will increase our understanding of mechanisms of IC-induced neutrophil recruitment and activation and provide therapeutic targets for antibody-mediated inflammation relevant to human disorders.